Despite an effective vaccine, measles virus (MV) is still the seventh leading cause of death worldwide. MV causes significant morbidity and mortality due to virus-associated immunosuppression and kills over 1 million children per year. Why is measles still a public health problem when a vaccine is available? The extremely infectious nature of the virus, interference with MV vaccination by maternally-inherited antibodies and waning immunity in vaccines all contribute to the stubborn resistance of MV to eradication. The interaction between viruses and cell-surface receptors is a major determinant of virus tropism and pathogenesis. For MV, the cell-surface receptor has been identified as the complement receptor CD46. The normal function of CD46 is to bind complement components on the cell surface and prevent their deposition on host cells. Previous studies have shown that complement C3b, the primary ligand for CD46, interacts with regions of the extracellular domain of CD46 near the membrane. Laboratory strains of MV, in contrast, interact with the N-terminal third of the extracellular domain of CD46. This interaction not only results in MV attachment and entry, but can also signal host lymphocytes to downregulate cytokine production. The long range goal of this project is to determine how wild-type measles virus (MV) interacts with the MV receptor CD46 to result in host-cell attachment, entry and modulation of intracellular signaling. First, emphasis is placed on mapping the specific interaction between wild-type strains of MV and the extracellular domain of the CD46 receptor. A combined molecular genetic and structural analysis will be used to identify and characterize the domains of the CD46 receptor that are responsible for interacting with wild-type MVs to achieve virus binding, entry and immunosuppressive effects in target host cells. A second emphasis of this grant is to characterize the signaling events that occur upon liganding of CD46 by wild-type and laboratory strains of MV and how these events regulate viral entry and immune function. Determining how the interaction between MV and CD46 influences intracellular signals is not only important for understanding how measles-induced immunosuppression occurs, but provides a potential tool for studying how virus-receptor interactions can modulate host cell function.